Mutations in the coagulation factor VIII gene result in a decreased or defective coagulation factor (FVIII) protein that gives rise to hemophilia A characterized by uncontrolled bleeding. Treatment of hemophilia A typically entails lifelong, multi-weekly intravenous infusion of either human plasma-derived or recombinant FVIII products. Patients treated with FVIII replacement products often develop neutralizing antibodies that render future treatment ineffective. Thus, there is a need to identify improved therapies.
Gene therapies are typically based on genetically engineered viruses designed to deliver functional transgenes to the patient so that their own cells can biosynthesize a missing or defective protein. Clinical advancements have been made using recombinant adeno-associated viral (rAAV) vectors for the expression of blood factors in the liver. McIntosh et al. report therapeutic levels of FVIII following administration of rAAV vector encoding a human factor VIII variant. Blood. 2013, 121(17):3335-44. See also Brown et al. Molecular Therapy, Methods & Clinical Development (2014) 1, 14036; Doering et al. J. Biol. Chem. 2004, 279:6546-6552; Zakas et al., J Thromb Haemost, 2015, 13(1):72-81; and U.S. Patent Application Publication US20040197875.
References cited herein are not an admission of prior art.